Glaucoma is a serious and growing health problem for our nation's Veterans. At least 285,000 Veterans (possibly over 700,000) have this chronic disease, the leading cause of irreversible blindness globally. Prevalence is greater among Veterans than in the general population and is increasing dramatically. Women Veterans and blast injury survivors are at higher risk for developing glaucoma as they age. Glaucoma is a serious problem for our nation's Veterans; we intend to do something about this. The greatest risk factors associated with glaucoma are elevated intraocular pressure (IOP) and age. Elevated IOP damages retinal ganglion cells (RGCs), causing blindness. Initially many patients respond well to topically-applied IOP-lowering drugs, but disease often returns over time. Given the aging Veteran population, there is thus an urgent need to develop new treatment strategies for late-stage disease. We propose a new, IOP-independent approach that directly protects RGCs by treating with a synthetic analog to Brain-Derived Neurotrophic Factor (BDNF) that we developed to protect RGCs from ocular blast injury, N-[2-(5-hydroxy-1H- indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC). We hypothesize that treatment with HIOC will slow or stop vision loss and protect RGCs in mouse models of glaucoma, including in aged mice. We propose two aims to test this hypothesis: Aim 1: To assess the feasibility of using a TrkB activator as a treatment for glaucoma, we will test whether HIOC treatment protects RGCs and vision in a mouse model of induced ocular hypertension. Hypothesis: TrkB activation by HIOC treatment will protect against RGC loss in a mouse model of induced, elevated IOP. IOP elevation will be induced by injecting microbeads into the ocular anterior segment to impede aqueous humor outflow. The resulting loss of RGCs and visual function mimics disease etiology observed in human glaucoma patients. HIOC will be given systemically by intraperitoneal injection at various times relative to induction and at various doses. Visual function, morphological, and toxicological outcomes will be assessed over time. To confirm that chronic, repeated HIOC treatment activates TrkB over time, the phosphorylation of TrkB and downstream mediators will be examined. Also, HIOC will be co-administered with a TrkB receptor antagonist to confirm protection specifically in a glaucoma model occurs through TrkB activation. Aim 2. To gain additional translational insight, test whether HIOC treatment is protective in a naturally- occurring glaucoma mouse model, the DBA/2J mouse. Hypothesis: TrkB activation induced by HIOC treatment will be protective in a naturally-occurring glaucoma model whose etiology includes late-onset, gradual elevation of IOP, RGC loss, and vision loss, as seen in human disease. The DBA/2J mouse develops pigment dispersion syndrome. Like many human glaucomas, the DBA/2J model is sporadic and progressive. This makes it a cumbersome model for testing multiple experimental permutations (as proposed in Aim 1), but a logical and powerful test for HIOC efficacy. To increase translational relevance, treatment will start after IOP elevation but prior RGC loss. These studies will test whether a BDNF TrkB receptor activator protects RGCs and vision in complementary mouse models of glaucoma. Similar to how we developed and brought another drug to trial (NCT02841306), this project contains proof-of-principle, mechanistic, and translationally-oriented experiments that will add to preclinical data in support of our proposing ophthalmic clinical trials of HIOC, a potentially inexpensive treatment for Veterans suffering from a currently intractable, chronic disease that results in blindness.